A Novel Susceptibility Locus On Chromosome 2 in the (New Zealand Black × New Zealand White)F1 Hybrid Mouse Model of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is inherited as a complex polygenic trait. (New Zealand Black (NZB) × New Zealand White (NZW)) F1 hybrid mice develop symptoms that remarkably resemble human SLE, but (NZB × PL/J)F1 hybrids do not develop lupus. Our study was conducted using (NZW × PL/J)F1 × NZB (BWP) mice to determine the effects of the PL/J and the NZW genome on disease. Forty-five percent of BWP female mice had significant proteinuria and 25% died before 12 mo of age compared with (NZB × NZW)F1 mice in which >90% developed severe renal disease and died before 12 mo. The analysis of BWP mice revealed a novel locus (χ2 = 25.0; p < 1 × 10−6; log of likelihood = 6.6 for mortality) designated Wbw1 on chromosome 2, which apparently plays an important role in the development of the disease. We also observed that both H-2 class II (the u haplotype) and TNF-α (TNFz allele) appear to contribute to the disease. A suggestive linkage to proteinuria and death was found for an NZW allele (designated Wbw2) telomeric to the H-2 locus. The NZW allele that overlaps with the previously described locus Sle1c at the telomeric part of chromosome 1 was associated with antinuclear autoantibody production in the present study. Furthermore, the previously identified Sle and Lbw susceptibility loci were associated with an increased incidence of disease. Thus, multiple NZW alleles including the Wbw1 allele discovered in this study contribute to disease induction, in conjunction with the NZB genome, and the PL/J genome appears to be protective.

Genetic Segregation of Spontaneous Erosive Arthritis and Generalized Autoimmune Disease in the BXD2 Recombinant Inbred Strain of Mice

“…The QTL near Chr 2 ( D2Mit412 ) has been shown to be close to the renal disease susceptibility locus in the (New Zealand Black × New Zealand White)F1 hybrid mouse model of systemic lupus erythematosus (Fig. 7A and Table 1) [23]. The QTL located on mouse Chr 4 (53.6 c m , identified by the D4Mit146 marker) is close to the autoimmune susceptibility or suppressor Sle2, Lbw2, Lmb1, Sles2, Nba1 and Asm2 loci that have been identified previously in mice with the NZM2410, NZB × NZW, B6, MRL and MRL‐lpr background (Fig.…”

A novel CD93 polymorphism in non-obese diabetic (NOD) and NZB/W F1 mice is linked to a CD4+ iNKT cell deficient state

“…The Cd93 locus is tightly linked to the diabetes susceptibility gene, Idd13 , and the Lupus susceptibility loci, Wbw1 and Nkt2 , in the region of 82–84 cM on mouse chromosome 2 (Esteban et al 2003; Jordan et al 2004; Rahman et al 2002). Both Idd13 and Nkt2 loci have been implicated in regulating the differentiation of natural killer T (NKT) cells, whose relative deficiency in NOD and NZB/W F1 mice is thought to play an important role in the pathogenesis of islet inflammation (Cain et al 2006; Chen et al 2007; Duarte et al 2004; Esteban et al 2003; Jordan et al 2004; Matsuki et al 2003; Poulton et al 2001; Rahman et al 2002; Wagner et al 2005). A subcongenic analysis by Chen et al revealed that there are at least two genes within Idd13 that regulate iNKT cell numbers and that NOD mice congenic for the B6 Idd13 locus were found to be protected from autoimmune diabetes progression associated with normalization of the NOD iNKT cell deficient phenotype (Chen et al 2007).…”

“…Interestingly, we also identified this Cd93 polymorphism in NZB/W F1 mice, to which the lupus susceptibility loci, Wbw1 and Nkt2 , are tightly linked (Rahman et al 2002; Esteban et al 2003). This point mutation is associated with aberrant expression of CD93 on NOD and NZB/W F1 B cells in the pro-/pre-, immature, and TR subsets as compared with non-autoimmune B6 mice.…”

“…This point mutation is associated with aberrant expression of CD93 on NOD and NZB/W F1 B cells in the pro-/pre-, immature, and TR subsets as compared with non-autoimmune B6 mice. The Idd13 and Wbw1 and Nkt2 loci are known to play a role in the regulation of the invariant natural killer T (iNKT) cell compartment (Chen et al 2007; Esteban et al 2003; Jordan et al 2004, Rahman et al 2002). Since NOD and NZB/W F1 mice are known to have deficiencies in their iNKT cell populations (Baxter et al 1997; Cain et al 2006; Chen et al 2007; Duarte et al 2004; Esteban et al 2003; Jordan et al 2004; Matsuki et al 2003; Poulton et al 2001; Rahman et al 2002; Wagner et al 2005), we sought to determine whether our finding of a mutation in the NOD and NZB/W F1 Cd93 gene is linked to regulation of iNKT cells in these autoimmune-prone strains.…”

Untitled

“…Genomic distribution of susceptibility intervals identified in linkage analysis on murine test crosses involving BSXB, MRL/l pr , PL/J, SWR, NZB, NZW, and NZM2410 strains [14,60,62,63]. …”